Cancer remains one of the most deadly threats to human health, affecting over 1 million new patients each year in the United States. Solid tumors are responsible for most of those deaths. Although there have been significant advances in the medical treatment of certain cancers, current methods of treatment are relatively non-selective: surgery removes the diseased tissue; radiotherapy shrinks solid tumors; and chemotherapy kills rapidly dividing cells. These treatments may result in numerous side effects, in some cases so severe as to limit the dosage that can be given and thus preclude the use of potentially effective drugs.
Angiogenesis is an important cellular event in which vascular endothelial cells proliferate, prune and reorganize to form new vessels from preexisting vascular networks. Angiogenesis is essential for the growth of most primary tumors and their subsequent metastasis. Vascular endothelial cell growth factor (VEGF), which is also termed VEGF-A or vascular permeability factor (VPF), has been reported as a pivotal regulator of both normal and abnormal angiogenesis. Ferrara and Davis-Smyth (1997) Endocrine Rev. 18:4-25; Ferrara (1999) J. Mol. Med. 77:527-543.
The anti-VEGF antibody “Bevacizumab”, also known as “BV”, “rhuMAb VEGF”, or “Avastin®”, is a recombinant humanized anti-VEGF monoclonal antibody generated according to Presta et al. (1997) Cancer Res. 57:4593-4599, which is currently approved in the U.S. for the treatment of metastatic colorectal cancer, non-small cell lung cancer, and metastatic breast cancer. Like other cancer treatments, Avastin® therapy is associated with certain side-effects, including an increased risk of hypertension.
Genetic polymorphisms occur in a population when different alleles in particular genes result in different phenotypes. Such polymorphisms may play a role in determining the efficacy and safety of therapeutic drugs. For example, specific polymorphisms in VEGF have been shown to be associated with the incidence of breast cancer. Schneider et al. (2008) Breast Cancer Research and Treatment 111:157-63.
Identification of additional polymorphisms predictive of the efficacy or safety of particular therapies may be used to better tailor therapies to those patients who would best benefit from them.